Human cytomegalovirus blocks canonical TGF β signaling during lytic infection to limit induction of type I interferons

Andrew H. Pham; Jennifer Mitchell; Sara Botto; Kara M. Pryke; Victor R. DeFilippis; Meaghan H. Hancock

doi:10.1371/journal.ppat.1009380

Human cytomegalovirus blocks canonical TGF β signaling during lytic infection to limit induction of type I interferons

Andrew H. Pham, Jennifer Mitchell, Sara Botto, Kara M. Pryke, Victor R. DeFilippis, Meaghan H. Hancock

Vaccine and Gene Therapy Institute

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFβ interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.

Original language	English (US)
Article number	e1009380
Journal	PLoS pathogens
Volume	17
Issue number	8
DOIs	https://doi.org/10.1371/journal.ppat.1009380
State	Published - Aug 2021

ASJC Scopus subject areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

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title = "Human cytomegalovirus blocks canonical TGF β signaling during lytic infection to limit induction of type I interferons",

abstract = "Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFβ interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.",

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AU - Pham, Andrew H.

AU - Mitchell, Jennifer

AU - Botto, Sara

AU - Pryke, Kara M.

AU - DeFilippis, Victor R.

AU - Hancock, Meaghan H.

N1 - Publisher Copyright: © 2021 Pham et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/8

Y1 - 2021/8

N2 - Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFβ interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.

AB - Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFβ interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.

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Human cytomegalovirus blocks canonical TGF β signaling during lytic infection to limit induction of type I interferons

Abstract

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